Artículo destacado

Drug News & Perspectives
Vol. 15, No. 10, 2002, pp. 647-653
ISSN 0214-0934
Copyright 2002 Prous Science, S.A.
CCC: 0214-0934/2002
http://www.prous.com

LOOKING AHEAD

We are entering an exciting period in the development of galanin pharmacology that may lead to new drugs for the treatment of cognitive decline and other neuro- and psychopathologies.

Galanin: Involvement in Behavior and Neuropathology, and Therapeutic Potential

by Peter J. McLaughlin and John K. Robinson

Summary

Since its discovery in 1983, the neuropeptide galanin has been found to be involved in a wide range of functions, including pain sensation, sexual activity, feeding, and learning and memory. Furthermore, galanin has recently been proposed to have a key role in depression, owing to its inhibition of noradrenergic cells, and in epilepsy. Three galanin receptor subtypes have been cloned and studied, though little is known about their specific contributions to behavioral processes. This article reviews galanin's role in behavior, with special attention to learning and memory. It concludes by discussing the status of the pharmacology of galanin, including nonpeptide ligands that have recently been developed with potential for therapeutic use, and the need for better receptor subtype-specific ligands. Despite the existence of many unknowns, the accumulation of basic research and the emergence of new research tools suggests we are entering an exciting period in the development of galanin pharmacology that may lead to new drugs for the treatment of cognitive decline and other neuro- and psychopathologies. © 2002 Prous Science. All rights reserved.

Galanin is a 29-amino acid or (in humans) 30-amino acid neuropeptide found in central and peripheral tissues. It was initially thought not to belong to any known family of peptides, though a galanin-like peptide has also been isolated recently¹ and found to have actions in the hypothalamus. Galanin, however, is the better studied of the homologues and, since its discovery in 1983,² has been found to subserve a variety of gastrointestinal^2­4 and neuroendocrine⁵ functions. A central nervous system role for galanin was clearly implicated when early studies identified extensive galanin-like immuno-reactivity and radiolabeled-galanin binding in rat brain.^6­8 The most dense labeling was in the hypothalamus (all hypothalamic nuclei are labeled), but other brain structures that showed high levels of galanin-like immunoreactivity and receptor binding included the amygdala, locus coeruleus, septum, basal ganglia, hippocampus and superior colliculus, as well as the prefrontal, piriform, periamygdalar and entorhinal cortical regions. Additionally, like many other neuropeptides, galanin is often found co-localized with monoamine neurotrans- mitters such as norepinephrine.

There are three known galanin receptors, all expressed in the central nervous system.⁹ GalR1 was the first galanin receptor to be cloned.^10,11 In situ hybridization revealed high concentrations of GalR1 mRNA in the dorsal root ganglia, dorsal horn of the spinal cord, olfactory bulb, amygdala, thalamus, hypothalamus (especially in the supraoptic nucleus), ventral extent of area CA1 of the hippocampus and subiculum.¹² Moderate signals were detected from the entorhinal cortex, as well as from the basal forebrain and locus coeruleus, with low levels in the dorsal raphe. In 1997, GalR2^13,14 and GalR3¹⁵ were cloned. GalR2 is believed to be expressed more diffusely than GalR1 throughout the brain. As with GalR1, the GalR2 receptor mRNA was found in dorsal root ganglion cells, the olfactory bulb, the spinal cord and the hypothalamus. Strong signaling was found in both the dorsal and ventral hippocampal dentate gyrus. Weak signaling was seen in the piriform and entorhinal cortex, but also in the neocortex, in contrast to the signaling with GalR1. Hybridization was also seen in the basal forebrain, substantia nigra, locus coeruleus and dorsal raphe, again suggesting a relationship with acetylcholine (ACh) and monoamine neurotransmitters.

The GalR1 subtype was found to activate mitogen-activated protein kinase via Gi protein signaling, whereas GalR2 may activate a number of second messenger systems. GalR2 increased inositol phosphate production by a Gq/G11 system and also demonstrated Go and Gi coupling.¹⁶ The diverse effects of GalR2 may mediate different effects on serotonergic cells, including hyperpolarization and decreased membrane resistance, as well as prolonging 5-HT_1A-mediated outward current.¹⁷ Similarly, galanin produces and prolongs potassium outflow in noradrenergic cells. Ericson and Ahlenius¹⁸ found that intracerebroventricular (i.c.v.) administration of galanin increased catecholamine and indolamine synthesis. Furthermore, it is believed that galanin, like many other neuropeptides, is released from cell bodies and dendrites as well as terminals.¹⁹ Together, these findings suggest that galanin is an important neuromodulator of "classical" neurotransmitters, serving generally as an inhibitor across a variety of systems.

The pattern of distribution suggests important modulatory roles of galanin in a variety of behavioral processes and potentially several neuropathologies. This article will review known effects of galanin in behavior and pathologies that may be ameliorated by future pharmaceutical intervention. As will be shown, galanin may have a crucial role in learning and memory, and in the cognitive impairments seen in Alzheimer's disease. Special attention will be given to these mnemonic effects, as galanin represents a still largely unexplored system for biotechnological and psychopharmaceutical development for learning or memory enhancement.

Role of galanin in behavioral processes and pathologies

Pain perception

O'Donnell and colleagues¹² have found a very high density of GalR1 and GalR2 mRNA in dorsal root ganglia, with more moderate signals from spinal gray. A role in transmission of somatosensory stimuli is thus implicated. Indeed, recent data suggest that exogenous galanin increases the number of action potentials of Ad and C fibers in response to noxious mechanical stimuli, but inhibit the same cells in a model of neuropathic pain.²⁰ Additionally, galanin knockout mice exhibited a decreased response to thermal pain,²¹ whereas mice that overexpress galanin showed an elevated heat nociceptive threshold, an effect that can be blocked by the galanin antagonist M35.²² Taken together, these findings suggest opposing roles for galanin in models of different nociceptive conditions and indicate that galanin receptor agonists as well as antagonists may be effective therapeutics in painful conditions.^23,24

Sexual behavior

Galanin administered intracerebroventricularly inhibits, while M35 facilitates, male sexual activity.²⁵ Further studies suggest that galanin inhibits opposite-sex approach, but not consummatory behavior.²⁶ On the other hand, galanin improved ejaculation latency and intromission frequency in sexually underperforming mice,²⁷ suggesting therapeutic efficacy for galanin in sexual dysfunction.

Feeding

Stimulation of food intake is one of the earliest known and best-studied behavioral effects of galanin; administration into the periventricular nucleus of the hypothalamus increases intake of fat in particular.^28­30 The neuromodulator leptin reduces both food intake and galanin in the hypothalamus,³¹ and recent work suggests that galanin is increased in carbohydrate- but not in fat-preferring rats, whereas leptin is higher in fat-preferring subjects.³² Interest in manipulation of the galanin system to combat dietary obesity has cooled in recent years because of the difficulty in developing drugs that can be delivered to the brain; although, as will be discussed, novel, nonpeptide ligands may prove useful in appetite regulation.

Seizure

There is considerable evidence accumulating suggesting that galanin is a potent natural anticonvulsant.³³ Galanin injected intracerebroventricularly, or into the hippocampus, caudate or substantia nigra, reduced picrotoxin-kindled seizures.³⁴ Induction of status epilepticus abolished galanin activity in the hippocampus, and exogenous galanin inhibited, while M35 facilitated, induction of status epilepticus, suggesting endogenous antiseizure activity.³⁵

Anxiety

Galanin increased behavior associated with anxiolysis in the punished drinking test at doses that do not impair locomotion or pain transmission.³⁶ On the other hand, the anta- gonist M40 decreased anxiogenesis by immobilization stress, perhaps by inhibiting stress-induced ACTH release.³⁷ It was found that i.c.v. administration of galanin reverses deficits in stepdown latency induced by the 5-HT_1A agonist, 8-OH-DPAT.³⁸

Depression

Recently, Weiss and colleagues³⁹ proposed that high-frequency stimulation of locus coeruleus cells induces galanin release onto dopaminergic soma in the ventral tegmental area, on the basis that a single depolarization of noradrenergic cells will increase, while burst firing will decrease, dopaminergic activity,⁴⁰ and that galanin may be released after only high-frequency firing.⁴¹ According to the proposed system, antidepressant drugs may act by blocked norepinephrine uptake, stimulating inhibitory autoreceptors, which in turn would decrease galanin release, thereby relieving inhibition of postsynaptic cells in the ventral tegmental area. Galanin affected dopaminergic responding in this area, producing motor slowing.¹⁸

Animal models also produce depression-like symptoms with decreasing levels of dopamine release from the ventral tegmental area, which Weiss and co-workers hypothesize as mediating the anhedonia in depression. However, the relationship between dopaminergic activity and depression in humans is unclear. Hypothesized mechanisms of anhe-donia involving the mesolimbic dopamine pathway are especially problematic, considering the evidence that this pathway does not mediate the primary reward value of food^42­44 or sex,^45,46 and thus has not been shown to be central to reported anhedonia in major depression. Nevertheless, the proposed system sets the stage for future work involving the interaction of monoaminergic and galaninergic modulation of chronic mood state. Techniques combining single-unit recording and pharmacological manipulation of behaving animals would address the role of selectively released galanin in depression.

Galanin involvement in learning and memory

To build a case for unequivocal involvement of galanin in learning and memory processes, one needs to apply several questions to the data: 1) Do manipulations of galanin cause a consistent pattern of deficits across a variety of methods of measuring learning or memory; 2) Are confounds (e.g., the effects of galanin on other behavior) properly controlled, or at least recognized and measured; 3) Does evidence gathered using tools that manipulate galanin truly mimic endoge- nous galanin actions (e.g., exogenous galanin application vs. antagonist studies); 4) Can effects be localized to brain structures (e.g., the hippocampus) implicated in the broader literature on learning and memory; and 5) Is there evidence for phylogenetic conservation in these systems that would lead us to generalize the effects in rodents to humans?

The effects of galanin on memory are perhaps the most widely studied of its behavioral profile. This may be due to two early findings. First, postmortem analysis of brains of persons suffering from Alzheimer's disease showed a high number of galanin-labeled cells in the nucleus basalis of Meynert in the basal forebrain, seen with a decrease in choline acetyltransferase in the same region.^47,48 The basal forebrain and septum provide the main cholinergic input to the cortex and hippocampus, and loss of efferents to the hippocampus is strongly associated with cognitive decline in Alzheimer's disease. Second, galanin appeared to be localized in cells that release ACh in the nucleus basalis of Meynert,⁴⁹ although recent work indicates that the vast majority of galanin-expressing forebrain cells do not express ACh in rats and humans.^50­52 Nonetheless, an antagonistic relationship is clear regarding memory. Indeed, exogenous galanin inhibits ACh release⁵³ and muscarinic ACh receptor-mediated phosphatidyl inositol hydrolysis⁵⁴ in the ventral hippocampus, the main target of the septohippocampal pathway. GalR2 mRNA was found in granule cells of the dentate gyrus, while GalR1 mRNA hybridization was found in pyramidal cells of Ammon's horn exclusively.¹²

Galanin and its synthetic antagonists have been found, both alone and in conjunction with other pharmacological probes, to modulate memory performance. Using the Morris water maze, galanin produced an impairment if administered during the first two training sessions, which was interpreted as an impairment in acquisition, but not retrieval.⁵⁵ However, the antagonist M35 was found to facilitate water maze acquisition and also retention after 7 days.⁵⁶ In the starburst maze, galanin also slowed learning.⁵⁷ Animals with nucleus basalis-medial septal lesions displayed amnesia on t-maze-delayed alternation that was attenuated by exogenous ACh. This effect was abolished by atropine but not mecamylamine, suggesting that the exogenous ACh improved memory by action at muscarinic receptors. Galanin was not found to affect delayed alternation per se, but potently inhibited the ACh improvement.⁵⁸ Intrahippocampal galanin deficits in spontaneous alternation in radial maze were also attenuated by glucose or the K_ATP channel blocker glibenclamide, an effect that may suggest an interrelationship;⁵⁹ however, as glucose and glibenclamide improved performance in absence of galanin, this channel blocker may affect memory via independent mechanisms.

Many of the studies of the amnesic effects of galanin have used the operant delayed non-matching-to-position paradigm (DNMTP), in which subjects are extensively pretrained, and potential motor and anxiety effects are minimized. Computed control allows for more precision in timing of events and in recording of many performance measures. In the DNMTP task, rats are trained when cued to press one of two levers mounted on a front panel, then remember which one was pressed. After a variable delay, the subject must nonmatch (i.e., select the nonsignaled lever) in order to receive a food or water reward. A key feature is that the impairment is considered to be selective for memory if and only if the extent of the deficit is correlated with the length of the delay; that is, performance is not disrupted when the delay is minimal, and error rate increases with the length of time the information must be retained. If a deficit is seen even at minimal delays, it suggests that a process other than or in addition to memory may be compromised.

Intracerebroventricular administration of galanin was found to interfere dose-dependently with nonmatching but in a delay-independent man- ner, suggesting that the effects of galanin on other behavioral processes may mask a memory effect.⁶⁰ Co-administration of galanin into the medial septum potentiated the delay-independent impairment of a moderate systemic dose of muscarinic receptor antagonist scopolamine, but had no effect on its own.⁶¹ This nonselective effect may not be unexpected, considering the involvement of galanin in various behavioral processes and the complex nature of DNMTP. When galanin was administered into the ventral hippocampus, the most pronounced impairments occurred at a long memory delay at low doses but not at high doses,⁶² suggesting that galanin may have a more specific effect on memory in the ventral hippocampus. Injecting galanin into this region, but not intraventricularly, produced a delay-dependent impairment in DNMTP performance that was blocked by the antagonist M40.⁶³

Recently, analysis of hippocampal sites revealed impairments in water maze performance with galanin infusions into GalR2-rich dentate gyrus but not Ammon's horn, in which GalR1 predominates.⁶⁴ Cholinergic lesions using 192IgG-saporin, a rodent model of Alzheimer's disease, produced a long-lasting (at least 11 weeks), delay-independent impairment on DNMTP performance, with reductions in cholinergic markers seen in the hippocampus, cortex and olfactory bulb, but not the caudate or cerebellum.⁶⁵ A significant correlation between hippocampal choline acetyltransferase levels and long- but not short-delay accuracy was found, further showing that galanin may modulate the memory mediation of ACh in the hippocampus, as well as cholinergic mediation of behavioral systems in other regions. Indeed, galanin inhibits tetanus- and q-induced long-term potentiation in area CA1, by a mechanism independent of glutamatergic or GABAergic transmission, perhaps by inhibiting conversion of short-term potentiation into long-term potentiation.⁶⁶ Taken together, these studies suggest that galanin in the hippocampus appears to mediate aspects of memory, while in other brain areas may mediate attentional, motivational, decision-making or other cognitive processes important for memory task performance.

However, while the evidence may be strong for a hippocampal involvement in galanin-induced memory-task impairments, the evidence that rules out other sites is not conclusive. An analysis of galanin administered into other sites of potential memory involvement produced no significant effects on the DNMTP task in the amygdala, nucleus basalis magnocellularis, or prefrontal or entorhinal cortex,⁶² but another study showed that the number of galanin binding sites increased with age in rats in the piriform and entorhinal cortex, ventral but not dorsal subiculum, and dorsal but not ventral dentate gyrus. Increases in binding were correlated with water maze impairment. No increase was seen in the septum, CA1, CA3 or amygdala.⁶⁷

Additional evidence for the involvement of galanin in learning and memory has come from the study of knockout and galanin-overexpressing transgenic mice.^68,69 Overexpression was associated with galanin hyperinnervation of basal forebrain neurons and a decrease in markers or ACh in the horizontal limb of the diagonal band, but not the medial septum, nucleus basalis or vertical limb of the diagonal band. The mice, while otherwise appearing normal in the general health and sensory-motor abilities, demonstrated impairments in the acquisition of the Morris water maze and in a social-olfactory memory task. Interestingly, galanin knockout mice showed evidence of loss of cholinergic basal forebrain neurons and accompanying memory deficits. It has recently been shown that rats administered galanin and mice overexpressing galanin exhibited similar patterns of freezing to a conditioned stimulus that had been previously paired with shock, demonstrating a correspondence between two very different methods of enhancing galanin levels in the central nervous system.⁷⁰

In conclusion, we can return to the questions presented at the beginning of this section. Indeed, there appears to be a consistent pattern of deficits across a variety of methods of measuring learning and memory, at least in rodents. This diversity of operational definitions of learning and memory provides information ranging from the role in spatial navigation (as in maze tasks) to the memory specificity of the operant DNMTP, in which confounds are minimized (e.g., the stress and swimming ability required to perform the Morris water maze task are not present). Additionally, researchers have generally been careful to analyze secondary, non-mnemonic measures of task performance to assess the degree of specificity of effects. Some evidence has been gathered that does not use the application of exogenous galanin to test hypotheses, but instead uses antagonists or genetic modifications to make inferences about the actions of endogenous galanin. However, much more work of this sort is needed. In terms of localizing the effects to memory-relevant brain structures, consensus is emerging that at least the hippocampus is involved in the galanin-induced deficits. However, this does not rule out important contributions from galanin systems in other structures to complex behaviors and tasks that are memory dependent. It is clear that behavioral work has not moved beyond rodents, probably be-cause of the lack of galaninergic drugs that can be administered systemically.

Future directions: Medicinal pharmacology and galanin

The evidence presented suggests that galanin is a neuromodulator involved in many behavioral processes including learning and memory. The potential to design nootropic

pharmacotherapies has been raised repeatedly.^71,72 The primary appeal of targeting galanin is to avoid some of the side effects of cholinergic or glutamatergic drugs. However, the pharmaceutical industry interest appears to be uneven.^73,74

Meanwhile, university researchers have worked on several promising avenues for drug development. High affinity galanin receptor antagonists were developed in the early 1990s at the University of Stockholm.^75,76 These were chimeric peptides that shared the N-terminal 1­13 amino acids of galanin but had different additional peptide sequences attached. They were shown to act as antagonists in a variety of in vitro and in vivo assays.^77­79 The therapeutic potential of galanin antagonists was demonstrated recently.⁸⁰ M40, when administered with muscarinic M₁ receptor agonist TZTP, attenuated 192IgG-saporin lesion-induced memory impairments. This suggested that galanin antagonists might boost the effectiveness of commonly used treatments for Alzheimer's disease.

The main limitations of these peptides are that they are all subject to degradation by peptidases and do not cross the blood­brain barrier. Re- cently, however, several nonpeptide galanin receptor ligands have been reported. One is a fungal metabolite, SCH-202596, that acts as an inhibitor on hGalR1, as measured in human Bowes melanoma cell membranes.⁸¹ Another class of GalR1 nonpeptide antagonists was discovered using a high-throughput assay by R.W. Johnson Pharmaceutical Institute. Researchers showed that the dithiin-1,1,4,4-tetroxide chemical series had high affinity for GalR1 receptors.⁸² A third compound, which is the best-studied to date, is a low-molecular weight, high-affinity galanin receptor ligand called galnon.⁸³ Galnon demonstrates agonist-like properties in a variety of assays. For example, it inhibited the activity of adenylate cyclase in the same manner as galanin. Galnon displaced galanin in an autoradiographic binding assay on spinal cord sections and was also a potent anticonvulsant in a variety of rodent seizure paradigms. To date, none of these ligands have been tested for effects on complex behavior or for subtype specificity.

The development of new, nonpeptide ligands that may also cross the blood­brain barrier is an exciting breakthrough. However, a critical problem for basic researchers remains in the lack of receptor subtype-selective ligands.⁸⁴ Previous antagonists have shown some specific affinity, but not enough to be useful in behavioral testing. In the short-term, various gene knockout or antisense mRNA knockdown⁸⁵ approaches show promise for the examination of receptor subtypes' involvement in behavior. The antisense approaches, which have developed slowly but steadily over the 1990s, may also have pharmaceutical applications if combined into hybrid molecules such as peptide nucleic acid antisense oligomers and can be modified to have blood­brain barrier and cell-penetrating characteristics.^86,87

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John K. Robinson, Ph.D., is in the Biopsychology Area, Department of Psychology, SUNY at Stony Brook, and Peter J. McLaughlin, Ph.D., is in the Department of Psychology, University of Connecticut, Storrs, CT 06269-1020 U.S.A; e-mail: pmclaugh@uconnvm.uconn.edu

Drug News & Perspectives Vol. 15, No. 10, 2002, pp. 647-653
ISSN 0214-0934 Copyright 2002 Prous Science, S.A. CCC: 0214 0934/2002 http://www.prous.com

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